Along with surgery and radiotherapy, chemotherapy continues to be an effective therapy for many cancers. In fact, several types of cancer are now considered to be curable by chemotherapy and include Hodgkin's disease, large cell lymphoma, acute lymphocytic leukemia, testicular cancer and early stage breast cancer. Other cancers such as ovarian cancer, small cell lung and advanced breast cancer, while not yet curable, are exhibiting positive response to combination chemotherapy.
One of the most important unsolved problems in cancer treatment is drug resistance. Drug resistance is the name given to the circumstance when a disease does not respond to a treatment drug or drugs. Drug resistance can be either intrinsic, which means the disease has never been responsive to the drug or drugs, or it can be acquired, which means the disease ceases responding to a drug or drugs that the disease had previously been responsive to.
Multidrug resistance is a specific type of drug resistance that is characterized by cross-resistance of a disease to more than one functionally and/or structurally unrelated drugs. Multidrug resistance in the field of cancer, is discussed in greater detail in "Detoxification Mechanisms and Tumor Cell Resistance to Anticancer Drugs," by Kuzmich and Tew, particularly section VII "The Multidrug-Resistant Phenotype (MDR)," Medical Research Reviews, Vol. 11, No. 2, 185-217, (Section VII is at pp. 208-213) (1991); and in "Multidrug Resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy," by Georges, Sharom and Ling, Advances in Pharmacology, Vol. 21, 185-220 (1990).
The drug resistance problem is a reason for the added importance of combination chemotherapy, as the therapy both has to avoid the emergence of resistant cells and to kill pre-existing cells which are already drug resistant.
Anthracyclines represent an important class of oncolytic agents. Doxorubicin, an anthracycline, which is also known in the art as ADRIAMYCIN.TM., is a drug of choice in the clinical management of breast cancer. Therapy with anthracyclines such as doxorubicin is complicated by the appearance of the anthracycline resistant phenotype which limits or negates the oncolytic activity of doxorubicin. Taxol.RTM. (paclitaxel) is an antineoplastic taxane derivative originally isolated from Taxus spp. yew tree. This compound, and later derivatives thereof, are useful in the treatment of metastatic ovarian carcinoma which is refractory to first-line chemotherapy.
Topoisomerase inhibitors represent a further class of oncolytic agents. Epipodophyllotoxins such as ETOPOSIDE.RTM. and TENIPOSIDE(.RTM.) are topoisomerase inhibitors which are useful in the therapy of neoplasms of the testis, small-cell lung and other lung, breast, Hodgkin's disease, non-Hodgkin's lymphomas, acute granulocytic leukemia and Karposi's sarcoma. The therapeutic utility of the epipodophylotoxins is limited by the appearance of the epipodophyllotoxin resistant phenotype.
One form of multi-drug resistance (MDR) is mediated by a membrane bound 170-180 kD energy-dependent efflux pump designated as P-glycoprotein (P-gp). P-glycoprotein has been shown to play a major role in the intrinsic and acquired resistance of a number of human tumors against hydrophobic, natural product drugs. Drugs that act as substrates for and are consequently detoxified by P-gp include the vinca alkaloids (vincristine and vinblastine), anthracyclines (Adriamycin), and epipodophyllotoxins (etoposide). While P-gp associated MDR is a major determinant in tumor cell resistance to chemotherapeutic agents, it is clear that the phenomenon of MDR is multifactorial and involves a number of different mechanisms. One such alternative pathway for resistance to anthracyclines involves the emergence of a 190 kD protein (p190)that is not P-gp. See T. McGrath, et al., Biochemical Pharmacolology, 38:3611 (1989). The protein p190 is not found exclusively on the plasma membrane but rather appears to be localized predominantly in the endoplasmic reticulum. See, e.g., D. Marquardt, and M. S. Center, Cancer Research, 52:3157 (1992).
The protein p190 possesses a nucleotide binding domain that is homologous with the ATP binding site of P-gp. See, D. Marquardt, et al., Cancer Research, 50:1426 (1990). The mechanism(s) utilized by p190 to confer resistance to ADRIAMYCIN.TM. is not well understood but may involve the intracellular redistribution of ADRIAMYCIN.TM. away from the nucleus. See, D. Marquardt and M.S. Center, supra. ADRIAMYCIN.TM. an inhibitor of topoisomerase II [W. T. Beck, Bulletins in Cancer, 77:1131 (1990)] which is an enzyme involved in DNA replication. Redistribution of ADRIAMYCIN.TM. away from the nucleus would therefore be an important component in cellular resistance to this drug. The studies published to date on p190 have utilized cell lines selected in vitro for resistance to ADRIAMYCIN.TM.. T. McGrath, et al., supra; D. Marquardt and M.S. Center, supra; and D. Marquardt, et al., Cancer Research, supra.
The association of p190 with drug resistance was made by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) of radioactive extracts prepared from Adriamycin-resistant HL60/Adr human leukemia cells labeled with 8-azido-alpha[.sup.32 P]ATP. See, T. McGrath, et al., supra. The drug-resistance phenotype conferred by p190 is not limited to the anthracyclines. Epipodophyllotoxin resistance is linked to p190 expression. The IC.sub.50 's of HL60/S cells treated with ADRIAMYCIN.TM. and ETOPOSIDE.TM. were 0.011 .mu.g/ml and 0.39 .mu.g/ml respectively. The IC.sub.50 's for HL60/Adr cells (a HL60-derived cell line which is resistant to doxorubicin) treated with Adriamycin and Etoposide were 2.2 .mu.g/ml and &gt;10 .mu.g/ml respectively. HL60/S and HL60/Adr cell lines do not express P-glycoprotein. HL60/Adr expresses p190. Thus, resistance to the anthracyclines and epipodophyllotoxins results from p190 expression.
It is, therefore, desirable to provide compounds which are useful for treating resistant neoplasms, the resistant pathway including p190, P-glycoprotein, or both.